Dehydroepiandrosterone (DHEA) Supplementation in Rheumatic Diseases: A Systematic Review

Background: Dehydroepiandrosterone (DHEA) is an adrenal hormone used to treat rheumatic conditions such as systemic lupus erythematosus (SLE), Sjogren’s syndrome (SS), rheumatoid arthritis (RA) with controversial results. Aim: To review the results of DHEA use in rheumatic diseases. Methods: PubMed, Scielo, Scopus, and Embase databases were systematically searched for articles on the treatment of rheumatic diseases with DHEA between 1966 and April 2023. Results: Twenty-one studies were identified: 13 in SLE, 5 in SS, 2 in RA, and 1 in fibromyalgia. DHEA use in SLE has shown a mild to moderate effect on disease activity, a positive effect on bone mineral density (BMD), and improved fatigue. The studies on SS showed a decrease in symptoms of dry mouth, but its performance did not differ from placebo in disease activity. In RA, a questionable effect on disease activity was noted. The only study on fibromyalgia failed to show any improvement. The drug was well tolerated; mild androgenic effects were the most common complaints. Conclusion: DHEA seems to have a place in SLE treatment, where it improves BMD and disease activity. The use in RA, SS, and FM is questionable.


INTRODUCTION
The immune and neuroendocrine systems are closely related, and this interconnection has reciprocal repercussions.][3] Dehydroepiandrosterone (DHEA) is a weak androgen secreted by the adrenal gland's zona reticularis.It is considered the most abundant steroid hormone in the plasma; it is a precursor of sex Dexamethasone and other glucocorticoids reduce serum levels of DHEA by suppressing the ACTH release. 57][8] This compound has anti-inflammatory and immunological properties; it inhibits the production of pro-inflammatory cytokines blocking the nuclear factor-kappa B (NF-kappa B) activation and increases the ratio of Th1/Th2 cytokines production. 9,10urthermore, it has anabolic properties in muscles, bones, and endothelium. 11Its supplementation has considerable effects on mood, well-being, and sexuality, improving the quality of life in patients with adrenal insufficiency and healthy elderly individuals. 12,13ow levels of DHEA have been noted in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren's syndrome (SS), suggesting a possible role for this steroid hormone in the treatment of autoimmune disorders. 14In rheumatic diseases, DHEA administration has been used in SLE, RA, SS, and fibromyalgia (FM), with results that are reviewed in the present paper.

Literature review
This article proceeded an extensive systematic search of articles published in the following four databases: PubMed/MEDLINE, EMBASE, Scopus, and Scielo from 1966 to April 2023 using the following MeSH entry terms: "dehydroepiandrosterone " OR "DHEA" OR "prasterone" AND "rheumatic" OR "rheumatologic" OR "systemic lupus erythematosus" OR "antiphospholipid syndrome" OR "vasculitis" OR "juvenile idiopathic arthritis" OR "fibromyalgia" OR "rheumatoid arthritis" OR "Sjögren's syndrome" OR "myositis" OR "systemic sclerosis" OR "spondylarthritis" OR "gout.We used equivalent strategies in other databases.No language restrictions were applied.The authors followed PRISMA guidelines. 15Eligibility criteria were human studies, observational, randomised controlled trials or non-randomised, cross-sectional, and case series.All with a prospective design.Animal experiments, in vitro studies, revisions, meta-analysis, and opinion papers were excluded.A standardised form to extract the following information from relevant articles was designed: authors, year of publication, number of studied patients, demographic data, disease duration, study follow-up, DHEA posology, outcomes, and side effects.The results were synthesised in two tables and no meta-analysis process was used.

RESULTS
Searching results are illustrated in Figure 1.Twenty-one studies were identified, most of them in SLE (13/21 or 61.9%), followed by SS (5/21 or 23.8%), two in RA (2/21 or 14.2%), and one in fibromyalgia (1/21 or 4.7%).which also studied males.The four main outcomes evaluated in this context were: disease activity, [16][17][18][19][20][21] symptoms, 20,22,23 serological markers, 21,24 and bone mineral density (BMD). 16,23,25,268,27 Only in the small study by Marder et al. 28 with 13 patients, improvement in disease activity measured by the SLEDAI could not be proved.Regarding the effects of DHEA on BMD, the results appear to be positive in the studies by Sanchez-Guerreiro et al. 26 and Mease et al. 25 as well as the effects on fatigue and general well-being.20,22,23 Nordmark et al. 23 also studied the effects of DHEA on sexual performance and observed some improvement.The study in the lipid panel showed a reduction of HLDc in at least three studies, 21,23,28 pointing to the fact that the DHEA effects on the lipid profile may not be beneficial. Most stuies in SLE used supraphysiological doses of DHEA (200-100 mg/day); [17][18][19][20][21][22][24][25][26][27] only one of them, by Nordmark et al. 23 evaluating parameters of quality of life, used small doses: 20-30mg/day.The drug was generally well tolerated, with mild side effects related to the androgenic action of this compound: acne and hirsutism. Alhough some serious complications were related during some trials, 16,20,26 they appear to be mostly due to the activity of lupus itself.In SS, the five studies encompassed 240 individuals, all females, and showed modest results.[29][30][31][32][33] (Table 2).Some improvement in dryness, fatigue, and quality of life was observed without differences compared to placebo.[29][30][31] Also, the two studies on RA were not reassuring; 34,35 both had a small number of patients (one with 11 and the other with 46 patients), and one used a low dose (50 mg/day) while the other used supraphysiological dose (200mg/day) of DHEA.The use of supraphysiological doses had led the RA patients to achieve ACR of 20% in 18% of patients, 35 while the other did not differ from placebo.34 The only study on fibromyalgia failed to show any benefit.5 (Table 2).

DISCUSSION
This study, reviewing the therapeutic effects of DHEA in rheumatic diseases, showed that, in SLE, this drug might have some indication.However, at the same time, in the other studied disorders: RA, SS, and FM, there is no evidence, so far, that this drug is helpful.In SLE, the sex hormones play a role in the aetiopathogenesis of the disease; androgens and DHEA are found to be reduced in almost half of the patients, 36 mainly in those with active disease. 37Moreover, in vitro studies have shown that this compound inhibits IL-6 and up-regulates IL-2, and studies in animal models of lupus; the administration of DHEA has led to a delay in the production of dsDNA autoantibodies as improved animal survival. 38,39In humans, it was not possible to prove that levels of the anti-dsDNA level changed with the DHEA treatment, 21 but several reports describe some effect on disease activity, 16,17,19 and that it decreases the number of flares. 16,20.This drug has also shown a beneficial influence on the BMD of lupus patients, even in patients receiving low-dose glucocorticoids. 25This is probably due to its conversion of DHEA into androgens and oestrogens and its action regulating inflammatory cytokines and tissue growth factors. 40,41he influence of DHEA on the circulatory system needs more attention.DHEA was thought to have beneficial aspects from the cardiovascular point of view.Previously, Bonet et al. 42 showed that it could avoid vascular remodelling by reducing cell proliferation and inducing apoptosis in proliferative cells.Lupus is known to be associated with endothelial dysfunction and premature cardiovascular disease, one of the leading causes of death in these individuals. 43In the general population, low levels of DHEA have been connected to amplified cardiovascular risk in men but not women. 44,45However, Marder et al. 28 could not prove that the use of this drug was advantageous in this context, even suggesting an opposite effect, with a trend towards impairment of endothelial function measured by brachial artery flow-mediated dilatation.It is essential to consider that the study by Marder et al. was small and did not consider the possibility of DHEA reducing glucocorticoid requirement.The effect of DHEA on lipid profile is a matter of care.In the study by Petri et al., 21 HDLc and low-density lipoprotein (LDL) cholesterol levels were reduced with DHEA.The changes in LDL cholesterol were considered minimal but significant in the HDLc, and 26.6% of their patients had HDLc values under 40 mg/dL by the end of the study.In the general population, it has been shown that high DHEA in men may increase cardiovascular mortality; 46 in females, no relationship between DHEA levels and coronary atherosclerosis could be found. 47So, more studies are needed in this context.Reduced serum levels of DHEA have also been found in SS; however, the local levels of sexual hormones seem to influence the functioning of glandular tissue. 48Androgen and oestrogen are produced in local tissues from DHEA through an intracrine process that is unique to human beings. 48Testosterone and oestradiol regulate the expression of several genes in lacrimal gland tissue, with testosterone having a positive effect on dry eye, while the impact of oestrogen remains unclear. 48Interestingly, the work by Porola et al. 49 showed that the DHEA treatment restored the plasma levels of androgens but did not correct the local deficiency in salivary glands, indicating a failure in the intracrine transformation of DHEA in SS. 32 Forsblad-d'Elia et al. 3 showed that the salivary flow TITLE rate did not increase with DHEA use despite improving subjective symptoms of oral dryness.General symptoms such as fatigue and feeling of well-being did not change in SS or FM patients.Finally, two papers analysed patients with RA, including 57 patients.This disease is associated with low testosterone and DHEA serum levels in males and postmenopausal females, 49 but the replacement showed a very modest effect in this setting.In general, the drug was well tolerated in most cases.Side effects were uncommon; most of them were androgenic effects such as acne and hirsutism, which were considered mild.The study strengths are: (1) inclusion of studies with patients with international criteria for rheumatic diseases; and (2) inclusion of all kinds of study designs on the use of DHEA in rheumatic disease.In this way, the authors believe that all published cases of DHEA in rheumatic patients were collected.Limitations were also observed.None of the studies reviewed compared DHEA with classical treatments used in rheumatic diseases.Most of them had a low number of participants and short follow-ups.Therefore, future studies, including larger samples and more extended observations, are warranted.This would enable a better understanding of the DHEA treatment in rheumatic conditions.Another limitation is that there is the possibility that a few articles might be not collected by the search process in a systematic review.

CONCLUSION
Few studies evaluate DHEA in rheumatological diseases, and only four such conditions were addressed in the literature: SLE, RA, FM, and SS.Most studies analysed in lupus demonstrated that DHEA use seems to have good effects on disease activity and BMD; results in RA, FM, and SS are disappointing.Side effects are mild and related to the androgenic effects.Therefore, DHEA may be a complementary option in patients with lupus, although future studies are indeed necessary to confirm these findings.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

FUNDING SOURCE
None.

AUTHOR CONTRIBUTIONS
JFC: Conception, acquisition, analysis, drafting, revision, submission EH: Analysis, revision TLS: Analysis, drafting, revision All co-authors take full responsibility for the integrity and accuracy of all aspects of the work.

Table 1
displays the SLE studies that encompass the DHEA IN RHEUMATIC DISEASES Figure 1.Search results.

Table 1 .
Not applicable.Studies on the use of dehydroepiandrosterone (DHEA) in systemic lupus erythematosus (SLE).

Table 1 .
Studies on the use of dehydroepiandrosterone (DHEA) in systemic lupus erythematosus (SLE).

Table 1 .
Studies on the use of dehydroepiandrosterone (DHEA) in systemic lupus erythematosus (SLE).

Table 2 .
Studies on DHEA use in rheumatoid arthritis, Sjögren's syndrome, and fibromyalgia.

Table 2 .
Studies on DHEA use in rheumatoid arthritis, Sjögren's syndrome, and fibromyalgia.